Synthesis and biological evaluation of new naphtho- and quinolinocyclopentane derivatives as potent melatoninergic (MT1/MT2) and serotoninergic (5-HT2C) dual ligands

Eur J Med Chem. 2017 Dec 1:141:552-566. doi: 10.1016/j.ejmech.2017.10.025. Epub 2017 Oct 12.

Abstract

We recently reported a series of naphthofuranic compounds as constrained agomelatine analogues. Herein, in order to explore alternative ethyl amide side chain rigidification, naphthocyclopentane and quinolinocyclopentane derivatives with various acetamide modulations were synthesized and evaluated at both melatonin (MT1, MT2) and serotonin (5-HT2C) receptors. These modifications has led to compounds with promising dual affinity and high MTs receptors agonist activity. Enantiomeric separation was then performed on selected compounds allowing us to identify levogyre enantiomers (-)-17g and (-)-17k as the highest (MT1, MT2)/5-HT2C dual ligands described nowadays.

Keywords: Agomelatine; Dextrogyre; Levogyre; Melatonin; Serotonin.

MeSH terms

  • Animals
  • Cell Line
  • Cricetinae
  • Cyclopentanes / chemical synthesis
  • Cyclopentanes / chemistry
  • Cyclopentanes / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Ligands
  • Molecular Structure
  • Receptor, Melatonin, MT1 / agonists*
  • Receptor, Melatonin, MT2 / agonists*
  • Receptor, Serotonin, 5-HT2C / metabolism*
  • Serotonin 5-HT2 Receptor Agonists / chemical synthesis
  • Serotonin 5-HT2 Receptor Agonists / chemistry
  • Serotonin 5-HT2 Receptor Agonists / pharmacology*
  • Structure-Activity Relationship

Substances

  • Cyclopentanes
  • Ligands
  • Receptor, Melatonin, MT1
  • Receptor, Melatonin, MT2
  • Receptor, Serotonin, 5-HT2C
  • Serotonin 5-HT2 Receptor Agonists